Pulmonary Tuberculosis: towards improved adjunctive therapies pptx

Front section: Glossary Glossary 6MWT 6 minute walk test 6MWWD 6 minute weight.walk distance AVDAPT Arginine and Vitamin D Adjunctive therapy in pulmonary tuberculosis BTA Basil taha

Front section: Author’s statement

Author’s statement

This thesis describes the development, implementation and preliminary results of the Arginine and Vitamin D Adjunctive Therapy in Pulmonary Tuberculosis (AVDAPT) randomised controlled trial

I had a central role in developing and implementing the study protocol collaboratively with my PhD supervisors Associate Professor Paul Kelly (Australian National University, Canberra) and Professor Nicholas Anstey (Menzies School of Health Research, Darwin), and with additional input from the investigators listed in Appendix 1 I wrote the initial draft of the study protocol for submission to the relevant ethics committees and for trial registration purposes (http://clinicaltrials.gov/show/ NCT00677339) I supervised and participated in the collection of data, performed the data analyses, wrote the thesis, and wrote all published and submitted manuscripts arising from the thesis The named co-authors made intellectual and writing contributions to the final manuscripts

One section of data analysis was not performed by me: the interim safety analysis described in Chapter 10 was conducted by an independent biostatistician (Mr Joseph McDonnell, Menzies School of Health Research) in his role as a member of the AVDAPT study Data and Safety Monitoring Committee

I am a named Chief Investigator on the successful National Health and Medical Research Council Project Grant Application 605806 entitled ―L-Arginine and Vitamin

D Adjunctive Therapies in Pulmonary Tuberculosis‖

_

Anna Ralph BMedSci, MBBS(Hons), MPH, DTM&H, FRACP

July 2010

Front section: Acknowledgements

Acknowledgements

I would like to acknowledge a number of people and organisations who have played significant roles in this research project I am very grateful to the National Health and Medical Research Council for providing a Postgraduate scholarship and a 2009 research grant, and the Australian Respiratory Council and the Royal Australasian College of Physicians (Covance award) which generously provided funds for the project

At the field research site in Timika, my very great thanks go to the research assistants Bapak Govert Waramori and Dr Gysje Pontororing, and director of the Timika Translational Research Facility Dr Enny Kenangalem, for their enthusiasm and commitment to the project, and for making the work so enjoyable Profound thanks also to all Timika Translational Research Facility staff who make the project possible: Ferryanto Chalfein, Prayoga, Daud Rumere, Frans Wabiser, Yeni, Henwi Pieris and Baspak Gobay (laboratory staff); Natalia Dwi Haryanti and Sri Hasunik (data management), Sri Rahayu (administration), and Gertruida Bellatrix and Hendrix Antonius (research assistants) Thanks also to Dr Daniel Lampah for medical and logistical help, and Maikel Zonggonau for driving, errands, and making sense of my limited Bahasa Indonesia At RSMM, I sincerely thank Dr Paulus Sugiarto for his support and for chairing the Data and Safety Monitoring Committee, and Dr Enny Malonda, for helpful discussions about TB management in Timika Dr Rini Poespoprodjo and Drs Franciscus Thio have also offered very valuable assistance for which I thank them very much Special thanks also to TB clinic staff Dr Andri Wiguna for medical support, Bapak Djonny Lempoy for frequent general assistance, and to Bapak Erstanto, Head, Timika TB laboratory, for diligently processing, recording and storing sputum slides for the study I also greatly thank Drs Pasi Pennitien, Michael Bangs, and Michael Stone (Public Health / Malaria Control, Timika), for their vital support across many tasks, including facilitating access to consumables and transporting specimens to Jakarta Finally in Timika, I am indebted

to all the study participants, healthy volunteers and their families for their involvement in the study

Front section: Acknowledgements

In Jakarta, I extend my thanks to colleagues at the Ministry of Health‘s National Institute of Health Research and Development who allowed this study to proceed In particular, I thank Dr Sandjaja for his assistance in facilitating the project, and his intellectual and practical input to the project; Dr Dina Bisara Lolong for contributing

to the development of the study protocol and visiting the field site, Ibu Merryani Girsang for contributing to laboratory quality control checks, and Dr Emiliana Tjitra for providing a co-ordinating role Major thanks to Dr Retno Soemanto and Mbak Yuni Rukminiati at the University of Indonesia Faculty of Microbiology for taking on the large task of processing all specimens collected for this project (culture / DST), and for being readily available for frequent discussions about results

In Darwin at Menzies School of Health Research (MSHR), I wish to convey deep thanks to my supervisor Professor Nicholas Anstey who has been a greatly valued mentor, and whose intellectual rigor is a constant inspiration His attention to detail and boundless reserves of optimism, tenacity and diplomacy mitigated many potential problems, solved the seemingly insoluble, and kept the project afloat He also provided greatly-appreciated contributions to the development of this thesis and the publications arising from it I greatly thank Dr Ric Price (PhD co-supervisor) for trying to impart to me some of his knowledge regarding statistics, data management and data analysis; the databases created for this thesis relied heavily on his assistance, and his detailed statistical advice was greatly appreciated Great thanks to Kim Piera for her meticulous approach to managing logistics and supplies, providing laboratory expertise, packaging medications, and helping with data entry, as well as providing good company in Timika Other laboratory personnel including Drs Tonia Woodberry, Gabriella Minigo and Jutta Marfurt have been extremely helpful in educating both myself and the Timika staff in laboratory methods, and striving to maintain good laboratory standards Administrative staff at MSHR essential to the operation of this project include Tania Paul, Ella Curry, Robi Cohalan, Asriana Kebon and Joanne Bex, to all of whom I am very grateful Also at MSHR, thanks to Associate Professor Peter Morris (PhD Advisor) for his major contributions to development of the study protocol, advice regarding the analytical plan, and input to devising a composite clinical outcome score; to Dr Nick Douglas for greatly-appreciated help and company in Timika; to Dr Tsin Yeo for statistical advice and for making available his data and knowledge on exhaled nitric oxide measurement; to Dr

Front section: Acknowledgements

Joshua Davis for friendly and comprehensible statistical advice; to Dr Louise Brown and Joseph McDonnell for their roles in the Data and Safety Monitoring Committee

Maple-At ANU, immense thanks to Associate Professor Paul Kelly who chaired my PhD supervisory panel It was through enthusiastic discussions with him in 2006 that I was inspired to embark on this research His earlier tuberculosis work in Timika and in other international settings provided a strong basis for the current project, and his contributions to discussions with collaborators in Timika and Jakarta have been vital for the project‘s operation I also sincerely thank Paul for making available to me the

TB data that he and others had previously obtained in Timika, for providing templates

on which I could model the study protocol and data collection forms, and for providing essential feedback on manuscripts, including this thesis My thanks also go

to Professor Niels Becker (PhD co-supervisor) for providing patient and detailed statistical help, especially in relation to the x-ray analyses and the exhaled nitric oxide correction factors, and to Dr Mark Clemens for his major assistance in the complicated factorial study sample size calculation To all other ANU staff who provided help (including Dr Robyn Lucas for vitamin D advice, and Sarah Geddes and Barbara Bowen for administrative help), to many fellow ANU PhD students who provided much-appreciated camaraderie and support, I convey my great thanks also

I also wish to sincerely thank Associate Professor Graeme Maguire, James Cook University (PhD Advisor), for support with supplies, logistics, lung function testing, data analyses, and occasional accommodation (snakes notwithstanding) I am very grateful for the important mycobacteriological advice and expertise provided by Mr Richard Lumb at the Institute for Medical & Veterinary Science, including his visits

to the Jakarta laboratory Many thanks also to Dr Cheryl Salome, Woolcock Institute

of Medical Research, for valuable exhaled nitric oxide advice and kind provision of materials Thanks also to Dr Mairwen Jones for proof reading sections of this thesis

Deepest thanks finally go to my partner Deborah for tolerating my absences and other difficulties this project has brought, and for supporting me unconditionally in every way

Front section: Figure

FIGURE 1: NIHRD-MSHR Timika research staff outside the research buidling

L to R: Front row Maikel Zonggonau, Enny Kenangalem, Sri Rahayu, Basbak Gobay, Hendrix

Antonius

Back row: Yani Reyaan, Wendelina Fobia, Anna Ralph, Frans Wabiser, Gysje Pontororing, Adol Fobia, Sri Hasunik Photo: Nick Anstey

Front section: Abstract

Abstract

The potential to improve pulmonary tuberculosis (PTB) treatment outcomes with adjunctive immunotherapies requires investigation L-arginine and vitamin D have antimycobacterial properties which render them suitable candidates Therefore the Arginine and Vitamin D Adjunctive therapy in Pulmonary TB (AVDAPT) trial evaluates these supplements in PTB This large trial commenced in June 2008 The project is run in Timika, Papua Province, Indonesia by the International Health Division, Menzies School of Health Research (Darwin, Australia), the National Institute for Health Research and Development (Ministry of Health, Indonesia), and the Australian National University (Canberra)

Aims of this thesis were to design and commence the AVDAPT study and examine baseline data Among the tested hypotheses were that exhaled nitric oxide (FENO), an L-arginine-derived antimycobacterial immunological mediator, would be elevated in PTB compared with healthy controls (HC), and inversely related to disease severity; secondly, that significant relationships would exist between different measures of TB severity

Consenting, eligible adults with smear-positive PTB were enrolled at the Timika TB clinic according to the protocol Assessments included sputum microscopy, culture and susceptibility, X-ray, weight, pulmonary function, FENO, 6-minute walk testing (6MWT) and quality of life (St George‘s Respiratory Questionnaire [SGRQ]) HC were enrolled for a single assessment

Results from 162 TB patients and 40 HC included: (1) findings pertaining to the trial (development / validation of outcome measures, and establishment of locally-relevant reference ranges for 6MWT and SGRQ); (2) findings pertaining to improved understanding of TB (demonstration of relationships between clinical, physiological, immunological [FENO] and functional measures of disease severity), and (3) investigation of TB drug-resistance and HIV rates

Front section: Abstract

A key finding was that FENO was not elevated in TB compared with HC and was lower still in worse disease These findings suggest that an impaired ability to generate adequate NO (e.g in L-arginine deficiency) might contribute to host inability

to adequately contain TB or mitigate lung pathology These findings support the rationale for conducting a trial of adjunctive L-arginine in TB

New relationships were identified between sputum smear grade, X-ray, weight, pulmonary function, 6MWT and SGRQ Patients with more-severe malnutrition had worse pulmonary function; 6MWT was independent of lung function; SGRQ results accurately captured people‘s perceived quality of life, correlating significantly with symptoms, 6MWT and pulmonary function; and sputum bacillary grade was significantly related to radiological extent and weight, but not to other results These findings support the use of a range of outcome measures in TB trials, to provide a comprehensive assessment of TB severity, rather than focusing on bacteriology alone

An x-ray severity score and a clinical outcome score were created, providing valuable tools for use in clinical trials Interim analysis confirmed the safety of L-arginine and vitamin D adjunctive therapy Multi-drug resistant TB rates remained low in new cases (2.0%), but HIV-TB co-infection rates rose significantly over 5 years, creating major challenges

This thesis provides the basis for continuation of the AVDAPT study, produces original findings relating to clinico-immunological aspects of PTB, and provides information of major local importance to help guide TB service provision in Timika

Front section: Glossary

Glossary

6MWT 6 minute walk test

6MWWD 6 minute weight.walk distance

AVDAPT Arginine and Vitamin D Adjunctive therapy in pulmonary tuberculosis

BTA Basil tahan asam (acid-fast bacilli)

Dinas Dinas Kesehatan (District Health Authority)

DOTS Directly Observed Treatment, Short-course

DSMC Data and Safety Monitoring Committee

FDC Fixed-dose combination antituberculous therapy

FENO Fractional exhaled nitric oxide

FEV1 Forced expiratory volume in 1 minute

FKUI Faculty of Microbiology, University of Indonesia

IMVS Institute for Medical & Veterinary Science

MDR-TB Multi-drug resistant TB

MGIT Mycobacterium Growth Indicator Tube

MIRU Micro-satellite Interstitial Repetitive Unit

MSHR Menzies School of Health Research (Darwin, Australia)

MTB Mycobacterium tuberculosis

NCEPH National Centre for Epidemiology & Population Health (Australia)

NHMRC National Health & Medical Research Council (Australia)

NIHRD National Institute of Health Research & Development (Indonesia)

NiOX FLEX Device for measurement of exhaled nitric oxide (non-portable)

NiOX MINO Device for measurement of exhaled nitric oxide (portable)

Puskesmas Pusat Kesehatan Masyarakat (Community Health Centre)

RSMM Rumah Sakit Mitra Mayarakat (Community hospital, Timika)

RSUD Rumah Sakit Umum Daerah (Regional General Hospital, Timika)

SGRQ St George‟s Respiratory Questionnaire

VCT Voluntary counselling and testing for HIV

XDR-TB Extensively drug-resistant TB

Tables of contents

Table of Contents

AUTHOR‟S STATEMENT I

ACKNOWLEDGEMENTS II ABSTRACT VI GLOSSARY VIII

1 AIMS 1

1.1 B ACKGROUND 1

1.2 A IMS 2

2 INTRODUCTION I: TUBERCULOSIS 1

3 INTRODUCTION II: ADJUNCTIVE TREATMENT IN TB 5

3.1 W HY ARE NEW TREATMENT APPROACHES NEEDED ? 5

3.2 ADJUNCTIVE THERAPIES 8

3.3 A RGININE AND VITAMIN D AS NOVEL POTENTIAL ADJUNCTIVE TREATMENTS IN TB 10

4 INTRODUCTION III: NITRIC OXIDE AND ITS MEASUREMENT IN VIVO 19

4.1 NITRIC OXIDE PATHWAYS 19

4.2 EXHALED NITRIC OXIDE MEASUREMENT 20

5 STUDY SETTING 26

5.1 T IMIKA FIELD RESEARCH FACILITY 26

5.2 T IMIKA TB C LINIC 28

5.3 O VERVIEW OF T IMIKA 29

5.4 C ONDUCT OF M EDICAL RESEARCH IN P APUA 34

5.5 C ONCLUSION 34

6 AVDAPT STUDY DESIGN AND METHODOLOGY 36

6.1 B ACKGROUND 36

6.2 H YPOTHESES 37

6.3 A IMS 37

6.4 M ETHODS 38

6.5 HEALTHY VOLUNTEER SUB - STUDY 65

7 RESULTS I: BASELINE DATA IN STUDY PARTICIPANTS AND HEALTHY VOLUNTEERS 67

7.1 I NTRODUCTION 67

7.2 M ETHODS 68

7.3 R ESULTS 70

7.4 D ISCUSSION 85

7.5 C ONCLUSION 93

8 RESULTS II: RELATIONSHIPS BETWEEN MICROBIOLOGICAL, CLINICAL AND FUNCTIONAL MEASURES OF TB SEVERITY 94

8.1 I NTRODUCTION 94

8.2 M ETHODS 95

8.3 R ESULTS 95

8.4 D ISCUSSION 100

8.5 C ONCLUSION 103

9 RESULTS III: MEASURING TB RADIOLOGICAL SEVERITY 104

Tables of contents

10 RESULTS IV: LONGITUDINAL FOLLOW UP 105

10.1 I NTRODUCTION 105

10.2 M ETHODS 107

10.3 R ESULTS 110

10.4 D ISCUSSION 123

10.5 C ONCLUSION 129

11 RESULTS V: EXHALED NITRIC OXIDE IN PULMONARY TB 131

11.1 I NTRODUCTION 131

11.2 M ETHODS 132

11.3 R ESULTS 134

11.4 D ISCUSSION 143

11.5 CONCLUSIONS 150

12 RESULTS VI: HIV-TB CO-INFECTION 152

12.1 I NTRODUCTION 152

12.2 M ETHODS 154

12.3 R ESULTS 155

12.4 D ISCUSSION 160

12.5 C ONCLUSION 163

13 CONCLUSIONS AND FUTURE DIRECTIONS 165

13.1 C LINICAL FINDINGS 166

13.2 HIV-TB AND MDR-TB TRENDS 168

13.3 C ONCLUSIONS FROM THE AVDAPT STUDY TO DATE 168

14 REFERENCES 171

15 APPENDICES 187

15.1 S TUDY I NVESTIGATORS 187

15.2 G OOD C LINICAL P RACTICE CERTIFICATION 189

15.3 T RIAL REGISTRATION 190

15.4 AVDAPT I NFORMATION AND CONSENT FORMS 191

15.5 AVDAPT DATA COLLECTION FORMS 195

15.6 S T G EORGE ‘ S R ESPIRATORY Q UESTIONNAIRE 205

15.7 A RGIMAX CERTIFICATE OF ANALYSIS 207

15.8 C ALCIFEROL S TRONG CERTIFICATE OF ANALYSIS 208

15.9 S AFTEY REPORTING PROCESS 209

15.10 S ERIOUS ADVERSE EVENT REPORT FORM 211

15.11 H YPERCALCAEMIA MANAGEMENT GUIDELINE 214

15.12 E XAMPLE OF E PI D ATA D ATABASE 216

15.13 H EALTHY V OLUNTEER I NFORMATION & C ONSENT FORM 217

15.14 H EALTHY VOLUNTEER DATA COLLECTION FORM 219

TABLES Table 2.1: Chronology of TB milestones 1

Table 4.1: Factors associated with abnormal exhaled nitric oxide 23

Table 6.1: Follow-up schedule for AVDAPT study participants 51

Table 6.2: Blood collection schedule for AVDAPT study participants 52

Table 7.1: Baseline characteristics of AVDAPT study participants (TB patients) and healthy volunteers 72 Table 7.2: Symptoms 74

Table 7.3: Baseline clinical findings and haemoglobin 75

Table 7.4: Baseline laboratory and radiological findings 79

Table 7.5: Agreement in sputum AFB grade 81

Table 8.1:Association between sputum smear grade at diagnosis and other measures of disease severity 96

Table 8.2: Regression coefficients from univariate linear regression models examining associations between clinical and laboratory measures* 97

Table 8.3: Correlation matrices showing correlation coefficients (top number) and p values (bottom number) for baseline clinical and laboratory measures* 98

Tables of contents

Table 10.1: Composite clinical outcome score 108

Table 10.2: Sputum MTB microscopy and culture results at baseline and 4 and 8 weeks 112

Table 10.3: Predictors of sputum culture conversion, univariate analyses 116

Table 10.4: Six-month treatment outcome 116

Table 10.5: Composite clinical outcome score at 8 weeks (end of intensive treatment phase) and 24 weeks (end of treatment) 117

Table 10.6: Correlations between outcome scores and percentage change in other measures 118

Table 10.7: Serious adverse events (SAE) 121

Table 10.8: Number of study participants with hypercalcaemia 122

Table 10.9: Summary of findings of the interim analysis 123

Table 11.1: Correlation between FE NO measures 134

Table 11.2: Corrections applied to exhaled nitric oxide readings obtained from the NiOX MINO portable analyser 137

Table 11.3: Characteristics and FE NO in healthy volunteers and TB patients at enrolment 138

Table 11.4: Summary of salient findings from the present study and previous investigations of exhaled nitric oxide in tuberculosis 149

Table 12.1: Characteristics of 138 study participants with known HIV status 156

Table ‎12.2: Treatment outcome in HIV positive and HIVnegative study participants 159

Table 12.3: TB-HIV coinfection management 160

FIGURES FIGURE 1: NIHRD-MSHR Timika research staff outside the research buidling v

Figure 4.1: NiOX FLEX 22

Figure 4.2: NiOX MINO 23

Figure 5.1: Map of Indonesia and Northern Australia showing Timika (Papua Province) 26

Figure 5.2: Timika community hospital (Rumah Sakit Mitra Masyarakat) 27

Figure 5.3: NIHRD-MSHR Timika research staff and visitors in the research buidling 28

Figure 5.4: Timika TB clinic and staff 29

Figure 5.5: Mimika district map 30

Figure 5.6: HIV education banner near RSMM hospital 34

Figure 5.7: Images of Timika 35

Figure 6.1: Diagrammatic representation of AVDAPT trial and related studies 39

Figure 6.2: Consent booklet 41

Figure 6.3: Enrolment procedure 44

Figure 6.4: Sample stickers applied to study medications 46

Figure 6.5: Spirometer calibration using 3 litre syringe 48

Figure 6.6: Mycobacterial growth indicator tubes (MGIT) 51

Figure 6.7: Sample processing at the NIHRD-MSHR research facility 53

Figure 7.1: Eligibility screening and enrolment of AVDAPT study participants 71

Figure 7.2: Smoking rates in male and female AVDAPT study participants and healthy volunteers* 73

Figure 7.3: Educational attainment in Papuan and Non-Papuan study participants* 73

Figure 7.4: Employment status in Papuan and Non-Papuan study participants 74

Figure 7.5: Symptoms reported among AVDAPT study participants at TB diagnosis 76

Figure 7.6: Number of symptoms reported at the time of TB diagnosis in men and women 76

Figure 7.7: Nutritional status in AVDAPT study participants 77

Figure 7.8: Haemoglobin according to sex, ethnicity, HIV status and in healthy volunteers versus TB patients overall 80

Figure 7.9: Educational attainment in healthy volunteers and TB patients* 82

Figure 7.10: Telephone ownership in TB patients and healthy volunteers 82

Figure 7.11: Employment status in TB patients and healthy volunteers 83

Figure 7.12: BMI in healthy volunteers and AVDAPT study participants 83

Figure 7.13: Six minute walk distances in healthy volunteers and AVDAPT study participants* 84

Figure‎7.14:‎St‎George’s‎respiratory‎questionnaire‎total‎score‎in‎healthy‎volunteers‎and‎AVDAPT‎study‎ participants* 85

Figure 8.1: Relationship between smear grade at TB diagnosis and CXR score and weight 96

Figure 8.2: Relationships between lung function impairment and weight, haemoglobin, illness duration and quality of life total score (SGRQ) 99

Figure 8.3: Relationship between number of reported symptoms and illness duration and quality of life (SGRQ) score 100

Figure 8.4: Illness duration in relation to educational attainment 100

Figure 10.1: Participant follow up profile 110

Tables of contents

Figure 10.2: Microscopy and culture results at enrolment, and 4 and 8 weeks in participants followed for

8 weeks 112

Figure 10.3: Kaplan-Meier survival curve showing probability of sputum smear conversion by ethnicity 114

Figure 10.4: Kaplan-Meier survival curve showing probability of sputum smear conversion by HIV status 114

Figure 10.5: Kaplan-Meier survival curve showing probability of sputum smear conversion by cavitary disease status 115

Figure 10.6: Kaplan-Meier survival curve showing probability of sputum smear conversion by baseline sputum AFB grade 115

Figure 10.7: Histograms demonstrating distributions of composite clinical outcome scores at 8 and 24 weeks 118

Figure 10.8: Non-serious adverse events experienced by AVDAPT study participants 120

Figure 10.9: Serial calcium readings in a representative individual receiving TB treatment and study medications 122

Figure 10.10: Ionised calcium (mean indicated by bar and range) by week in AVDAPT study participants 122

Figure 11.1: Bland-Altman plot: repeated exhaled nitric oxide measures on single analyser 135

Figure 11.2: Bland-Altman plot: paired exhaled nitric oxide measures on 2 analysers 135

Figure 11.3: Bland-Altman plot: paired exhaled nitric oxide measures on the NiOX MINO (portable analyser)‎and‎NiOX‎FLEX‎(‘gold‎standard’) 136

Figure 11.4: Relationship between exhaled nitric oxide measures on the Niox Mino and Niox Flex 136

Figure 11.5: Exhaled nitric oxide in healthy volunteers and TB patients at week 0 and during TB treatment 140

Figure 11.6: Exhaled nitric oxide according to sex in TB patients at week 0 141

Figure 11.7: Exhaled nitric oxide according to weight in TB patients at week 0 141

Figure 11.8: Correlations between change in FE NO and clinical outcome score at weeks 8 and 24 142

Figure 12.1: Rates of HIV-TB co-infection among study participants 157

Figure 12.2: HIV-TB co-infection rates in Timika in 2003-4 compared with 2008-9 158

Figure 12.3: Meeting between AVDAPT research personell and local HIV care providers 164

BOXES Box 3.1: Actions of Vitamin D 13

Box 4.1: Principles of exhaled nitric oxide measurement 21

Box 5.1: Approvals required for conducting medical research in Papua, Indonesia 35

Box 6.1: Explanation regarding planned off-shore laboratory analyses 55

Box 7.1: Definitions 69

Box 7.2: Locally-relevant reference ranges for 6-minute walk testing 85

Box 10.1: AVDAPT study primary outcome measures 106

PUBLISHED AND SUBMITTED MANUSCRIPTS Manuscript 1: Ralph AP, Anstey NM, Kelly PM Tuberculosis into the 2010s: is the glass half full? Clin Infect Dis 2009;49(4):574-83 3

Manuscript 2: Ralph A, Kelly P, Krause V What's new in TB? Australian Family Physician 2009; 38(8):578-585 4

Manuscript 3: Ralph AP, Kelly PM, Anstey NM L-arginine and vitamin D: novel adjunctive immunotherapies in tuberculosis Trends Microbiol 2008;16(7):336-44 15

Manuscript 4: Ralph AP, Ardian M, Wiguna A, Maguire GP, Becker NG, Drogumuller D, Wilks MJ, Waramori G, Tjitra E, Sandjaja, Kenangalem E, Pontororing GJ, Anstey NA, Kelly PM A simple, valid, numerical score for grading chest X-ray severity in adult smear positive pulmonary tuberculosis Accepted, Thorax, July 2010 104

Chapter 1: Aims

1 Aims

1.1 BACKGROUND

Mycobacterium tuberculosis (MTB) is one of the most successful human pathogens It

infects an estimated third of the human population, and currently accounts for the greatest number of deaths from a curable infectious disease.1, 2 Tuberculosis (TB) is an

historical disease whose existence may pre-date Homo sapiens,3 but it maintains major contemporary relevance It re-emerged as a ‗global emergency‘ by the turn of the 21stcentury, and now is defying reduction targets in parts of the globe worst-affected by the overlapping pandemics of TB and HIV.2 New case numbers are estimated at around 9.3 million annually.2 Antibiotic treatment regimens for TB, largely unchanged in the last four decades, are cumbersome and protracted, contributing to cure rates frequently falling short of the 85% target set by the World Health Organisation (WHO).4 Innovative strategies therefore require investigation for their potential to accelerate responses to antibiotics, with the ultimate goals of reducing required TB treatment duration, reducing the period of infectivity, permitting earlier return to employment or school, and reducing post-TB residual lung pathology

Recognising this priority research field, the AVDAPT (Arginine and Vitamin D Adjunctive therapy in Pulmonary TB) clinical trial investigates the use of L-arginine and vitamin D as immunotherapies supplementary to conventional TB treatment in pulmonary TB This is a large randomised, double-blind, placebo-controlled trial which commenced in June 2008 and is projected to complete enrolments in early 2012, at the Timika Translational Research Facility in Papua, Indonesia, through Menzies School of Health Research‘s (MSHR) International Health Division in partnership with the National Institute for Health Research and Development (NIHRD), Indonesian Ministry

of Health, and the Australian National University (ANU)

Chapter 1: Aims

1.2 AIMS

The aim of this thesis is to design and implement a clinical trial of the safety and efficacy of L-arginine and vitamin D as adjunctive therapies in pulmonary TB (the AVDAPT study) This includes methodological objectives (Aim 1) and analytical objectives (Aims 2 to 8)

In detail, this comprises development of methodologies relevant to operating the trial, testing of hypotheses regarding the validity of the measures used in the study, examination of data collected during the initial phase of study participant recruitment and follow up (June 2008 - October 2009), and determination of longitudinal epidemiological trends by comparing current data with an historical cohort at the same site

Final results of the AVDAPT study will be presented at completion of the trial, anticipated to be in 2012

AIM 1: DESIGN AND COMMENCE THE AVDAPT RCT

The first objective is to design and commence the AVDAPT RCT This study aims to determine whether supplementation with L-arginine and / or vitamin D is safe and effective in TB, where efficacy includes more rapid improvement in clinical, mycobacterial, immunological, radiological, physiological and / or functional measures

of treatment outcome In order to gain understanding of the underlying immunology of relevance to this trial, the AVDAPT study further aims to determine whether exhaled nitric oxide (FENO) is inversely related to disease severity The detailed aims of the AVDAPT trial are set forth in Chapter 6 (Methods) The hypotheses investigated in this study include:

Hypothesis 1(a): That L-arginine supplementation in pulmonary TB will be safe, will

increase plasma arginine concentrations, will enhance pulmonary production of nitric oxide (NO) (a key arginine-dependent immunomodulator and downstream immune mediator of mycobacterial killing) and will improve the rapidity and magnitude of the microbiological and clinical response Baseline pulmonary NO production will be elevated in pulmonary TB but inversely associated with disease severity Both

Chapter 1: Aims

baseline and post-treatment increments in exhaled NO will be associated with rapidity and magnitude of the treatment response

Hypothesis 1(b): That supplementation with vitamin D, the metabolite of which

(1,25-dihydroxyvitamin D3) has anti-mycobacterial activity, will be safe, will increase plasma vitamin D concentrations, and will improve the rapidity and magnitude of the treatment response in human PTB

AIM 2: INVESTIGATE BASELINE CHARACTERISTICS OF TB STUDY

PARTICIPANTS AND HEALTHY VOLUNTEERS

Aim 2(a): to explore the baseline demographic characteristics of AVDAPT study

participants, and present clinical and laboratory findings at the time of their enrolment

into the study, including results of Mycobacterium tuberculosis susceptibility testing

Aim 2(b): to establish reference ranges for exercise tolerance (six-minute walk test) and

a quality of life score (modified SGRQ), by performing these tests in locally recruited healthy volunteers, for comparison with values obtained in TB patients (AVDAPT study participants)

AIM 3: INVESTIGATE RELATIONSHIPS BETWEEN MICROBIOLOGICAL, CLINICAL AND FUNCTIONAL MEASURES AT BASELINE

Aim: to describe the relationships between clinical (symptoms and weight),

mycobacterial (sputum smear grade), physiological (spirometry) and functional minute walk test, SGRQ) measures, and to investigate any associations between socio-economic indicators and diagnostic delay or disease severity

(six-Hypotheses: That clinical and functional measures of TB disease severity at enrolment

will significantly relate to bacteriological (sputum smear grade) measures

Specifically, that baseline weight, FEV1 and six-minute walk test will be inversely

related, and modified SGRQ score, cough severity and number of symptoms will be

directly related, to sputum smear grade Also, that clinical, functional and

physiological measures of TB disease severity at enrolment will significantly correlate with each other

Chapter 1: Aims

AIM 4: MEASURE RADIOLOGICAL SEVERITY OF TB

Aim: To develop a valid method by which to grade chest X-ray severity in study

participants with pulmonary TB, using a previously-collected dataset from a similar sample of adults with pulmonary TB in Timika, and to further examine the ability of this score to predict baseline clinical and microbiological severity and 2 month outcomes in AVDAPT study set

Hypothesis: that a numerical score applied to an X-ray can provide a means of

evaluating baseline severity and response to treatment

AIM 5: DEVELOP A COMPOSITE CLINICAL OUTCOME MEASURE

Aim: to develop a composite clinical outcome score calculable at 2 and 6 months, and

determine the relationship between this and microbiological, radiological and functional measures of TB severity

Hypothesis: That a composite clinical outcome score at 2 and 6 months will be

significantly related to microbiological, radiological and functional measures

AIM 6: EVALUATE INTERIM OUTCOMES

Aim: to document treatment outcomes among study participants, including sputum

smear and culture conversion, and provide interim adverse event and safety data relating

to the AVDAPT study

AIM 7: MEASURE EXHALED NITRIC OXIDE IN PULMONARY TB

(bacteriological, radiological and clinical) at TB diagnosis; to compare FENO measures from pulmonary TB patients with measures from contemporaneously evaluated local healthy controls and an historical healthy control group from the same research site; and

to determine longitudinal changes in FENO in response to TB treatment

Chapter 1: Aims

with healthy controls, will be inversely related to disease severity at baseline, and will

return towards normal by the end of therapy

AIM 8: EPIDEMIOLOGY OF HIV – TB COINFECTION

Aim: to describe the current epidemiology of HIV-TB co-infection in Timika, and

compare the HIV-TB co-infection rates in 2008-2009 with 2003-2004 (a time period for which previous HIV-TB co-infection rates are published)

Chapter 2: Introduction 1: Tuberculosis

2 Introduction I: Tuberculosis

TB has been the subject of recent comprehensive reviews.5-7 My approach to reviewing the literature in this introductory chapter is therefore to summarise milestones in TB understanding and management (Table 2.1), and to focus on two specific questions: 1) What recent progress has been made globally in TB control? 2) What should Australian practitioners know about contemporary TB management? These questions are addressed, respectively, in publications reproduced hereafter: ―TB into the 2010s: is the glass half full?‖8

and ―What‘s new in TB?‖.9

Table 2.1: Chronology of TB milestones

1882 Robert Koch (German physician), announced his identification of Mycobacterium

tuberculosis as the causative agent of TB on March 24th, now commemorated as World TB Day

1882 German pathologists Ziehl and Neelsen introduced a staining method using

carbolfuchsin, an acid wash, and methylene blue to demonstrate the presence of fast bacilli

acid-1890 Description of tuberculin by Koch, trialed (unsuccessfully) to treat TB

1895 Discovery of x-ray techniques for diagnostic purposes by Conrad Roentgen, providing

an important additional diagnostic tool for pulmonary TB

1905 Koch received Nobel Prize in Physiology or Medicine

1921 Development of vaccine, now known as BCG, from attenuated Mycobacterium bovis

by Calmette and Guerin

1940s Roll-out of mass TB vaccination using BCG

1944 Streptomycin (SM) and Para-amino salicylic acid (PAS) discovered as effective

antimicrobial therapies for the treatment of TB

1947-1948

First randomised curative trial to be conducted in the UK was performed, evaluating

SM as an anti-tuberculosis agent

1952 Addition of isoniazid (INH) to SM and PAS shown to increase cure rates from 70 to

95%, but required treatment for 18-24 months

1959 Madras study showed domiciliary treatment to be as good as in sanitaria, and not

resulting in more TB cases in family contacts, allowing TB treatment to be shifted to the community

1965 Rifampicin discovered, leading to the advent of short course combination therapy

Chapter 2: Introduction 1: Tuberculosis

1969 Given successes in the management of TB and other infectious diseases, U.S

Surgeon General William Stewart famously stated in his address to Congress it was time to “close the book on infectious diseases” This prevailing attitude led to TB- specific control being dismantled in many countries during the 1970-80s

1981 HIV pandemic first recognized

1985 TB incidence in the USA began to rise for first time in 30 years, described as an

unprecedented resurgence during 1985-1992

1991 World Health Organisation (WHO) specifies targets for case detection and cure: detect

at least 70% and cure at least 85% of smear-positive TB cases

1991 WHO Directly Observed Therapy, Short Course (DOTS) strategy rolled out (officially

named „DOTS‟ in 1994) comprising: (1)Political commitment with increased, sustained financing; (2) Case detection through quality-assured bacteriology; (3) Standardized treatment, with supervision and patient support; (4) An effective drug supply and management system; (5) Monitoring and evaluation system, and impact measurement

1992 Multi-drug resistant (MDR)-TB identified as a major new threat in New York City

1993 World Health Assembly declared TB a “Global Emergency”

2003 Early guidelines released on the use of interferon gamma release assays for latent TB

diagnosis; understanding of test interpretation evolved during the reminder of the decade

2006 Extensively drug-resistant TB labeled „XDR-TB‟ XDR-TB / HIV co-infection in

Kwa-Zulu Natal province, South Africa, reported to have near 100% fatality

2006 Stop TB partnership launched

2008 WHO endorsed the use of rapid molecular resistance detection tests, able to provide

MDR-TB diagnosis in 1-2 days

2008 MDR and XDR-TB cure rates of >60% reported

2008 Mortality significantly reduced in HIV-TB co-infection by commencing antiretroviral

therapy during TB treatment instead of deferring until after TB treatment

2009 Positive results from drug trials (e.g moxifloxacin, TMC207) provide optimism for

improvements of standard TB regimens and MDR-TB treatment

Table 2.1 references5,10-20

Chapter 2: Introduction 1: Tuberculosis

Manuscript 1: Ralph AP, Anstey NM, Kelly PM Tuberculosis into the 2010s: is the glass half full?

Clin Infect Dis 2009;49(4):574-83

<see paper next page>

R E V I E W A R T I C L E

Tuberculosis into the 2010s: Is the Glass Half Full?

Anna P Ralph, 1,4 Nicholas M Anstey, 1,2,3 and Paul M Kelly 1,4

1 International Health Division, Menzies School of Health Research, 2 Charles Darwin University, and 3 Division of Medicine, Royal Darwin Hospital,

Darwin, and 4 National Centre for Epidemiology and Population Health Research, College of Medicine, Biology and Environment, Australian

National University, Canberra, Australia

During the 16 years since the World Health Organization declared tuberculosis (TB) a global emergency, major

new challenges have emerged—in particular the spread of extensively drug-resistant (XDR)-TB and its overlap

with human immunodeficiency virus infection However, during this period, we have also witnessed the creation

of—and major commitments from—agencies dedicated to TB control, research, and funding, and tangible

positive achievements have occurred; these include improvements in both new and existing TB diagnostics,

a developmental pipeline of new candidate TB drugs, better treatment outcomes for multidrug-resistant TB

and XDR-TB, heightened recognition of the importance of nosocomial transmission, and improved strategies

to reduce mortality associated with concurrent human immunodeficiency virus infection and TB We suggest

updates to the 2006 International Standards of Tuberculosis Care to embrace these developments The

in-corporation of these recent advances into optimized directly observed treatment, short course (DOTS),

pro-grams, in conjunction with more widespread deployment and enhanced political will, all provide grounds for

improved control.

Mycobacterium tuberculosis is the consummate human

pathogen Millennia of evolution alongside human

hosts have led to elaborate immune evasion and

trans-mission strategies [1, 2]; as such, M tuberculosis is

thought to infect one-third of humans, and in 2007, it

accounted for an estimated 9.27 million new cases of

tuberculosis (TB) and ∼1.7 million deaths [3]

Com-pounding this already crippling burden are the

ex-panding threats of TB drug resistance and of concurrent

human immunodeficiency virus (HIV) infection and

TB Primary transmission is the most common mode

of acquisition seen in some settings for both extensively

drug-resistant (XDR) and multidrug-resistant (MDR)

TB [4–6] The overlapping of HIV and TB epidemics

in sub-Saharan Africa in particular creates a health care

crisis and renders it unlikely that the Millennium

De-Received 27 January 2009; accepted 24 April 2009; electronically published 7

July 2009.

Reprints or correspondence: Dr Anna Ralph, International Health Division, School

of Health Research, PO Box 41096, Casuarina NT 0811, Australia

(annaralph@bigpond.com).

Clinical Infectious Diseases 2009; 49:000–000

 2009 by the Infectious Diseases Society of America All rights reserved.

1058-4838/2009/4904-00XX$15.00

DOI: 10.1086/600889

velopment Goal 6.C of reduction in TB prevalence and mortality by 50% by 2015 will be achievable in this region [7, 8].

Amid these grim realities, however, exciting recent developments with the potential to bring about im- portant reductions in TB-related burden of disease have been achieved, including in achievements in under- resourced settings However, their implementation poses new challenges due to resource constraints, pol- icy-change inertia, and the need to prioritize basic TB care, as articulated by the World Health Organization’s (WHO’s) directly observed therapy, short-course (DOTS), and Stop TB partnership strategies [9, 10] As has been clearly articulated, it is incumbent upon those with expertise and resources to take a serious role in bringing these developments into action in under- resourced TB-burdened settings [11] Indeed, investing

in TB control in resource-poor settings might be more cost-effective for developed nations in improving their own TB control than alternative approaches [12].

The TB literature is characterized by bleak statistics that provide substance for, in health-promotion terms,

“fear-based” appeals; there is merit in directing tion in this manner to the dire global state of TB How- ever, there is an equal place for the alternative approach

atten-of positive appeals as effective strategies to promote a shift in

mindset and uptake of new practices [13] Here, we review

important recent gains made in TB management and

knowl-edge, discuss how these might be incorporated into existing

DOTS programs, suggest a revision of several standards

con-tained within the comprehensive 17-point 2006 International

Standards of TB Care (ISTC), and recommend an 18th

Stan-dard [14] Contrasting with negative appeals, we show that

there is scope for optimism.

TB DIAGNOSTICS

Rapid recent developments have occurred in the field of TB

diagnostics, as evidenced by the need to establish a subgroup

within the Stop TB Partnership’s New Diagnostics Working

Group to provide ongoing systematic reviews of diagnostic

methods (Table 1) [15].

Of greatest priority are affordable ways to improve case

de-tection through smear microscopy at field laboratories Simple

procedures recently shown to be of benefit include more clear

instruction of people on how to produce an adequate sputum

specimen [16], a reduction in the required number of

speci-mens from 3 to 2 [17], more rapid specimen collection [18],

and the processing of sputum specimens prior to examination

(Table 1) [15, 19] Fluorescence microscopy is more sensitive

and rapid than conventional microscopy [19], and a

light-emit-ting diode light source has recently been shown to be a reliable

alternative to the expensive, short-lived mercury vapor lamps

[20] Such approaches provide solutions to the valid assertion

that substandard TB diagnostics are unacceptable in

resource-poor countries [11].

Transportation of specimens to a reference laboratory can

be achieved despite challenging barriers: fresh sputum samples

can be stored at 4C for up to 6 weeks before unrefrigerated

transportation, achieving excellent M tuberculosis recovery

without excessive contamination [21] At laboratories with

ad-equate capacity, early resistance detection—a critical tool in

prevention of resistance amplification that is associated with

better treatment outcomes for management of MDR-TB [22]—

is now achievable with rapid molecular and culture-based

methods Line-probe assays (eg, Genotype MTBDRplus assay

[Hain Lifescience]), which detect M tuberculosis gene

muta-tions that confer resistance to rifampicin (rpoB) and isoniazid

(katG and inhA), provide sensitive and specific results in 6 h

to 2 days [23–25] Culture-based rapid methods for resistance

detection are outlined in Table 1.

These improvements over traditional direct Ziehl-Neelsen

staining and use of solid-culture media require rapid

dissem-ination and uptake Promotion of new technologies, via WHO

endorsement [25], inclusion in guidelines [26], or

internation-ally accepted standards [14], is the first step in their

deploy-ment, but innovative means are required to traverse the

for-midable barriers to dissemination of these messages to national

TB control programs and the practitioners who implement these programs.

NEW DRUG REGIMENS

New anti-TB drugs are required to permit shorter treatment durations for drug-susceptible TB [27], which mathematical modeling indicates could effect major reductions in TB inci- dence and mortality [28], and to provide less toxic, more ef- fective, and shorter regimens for MDR-TB The TB literature has long lamented the absence of new drug developments since rifampicin in the 1960s Barriers to TB drug development in- clude the need to evaluate drugs in combination over long follow-up periods in resource-limited settings; a lack of good animal models for preclinical drug evaluation [29]; metabolic

adaptability of M tuberculosis, whereby genetic targets that

ap-pear promising have not proven to be so [30]; and the ception by pharmaceutical companies that antibiotic devel- opment is unrewarding [31] Modeling performed in 2006 that incorporated the high attrition in drug development, found only a 5% chance of a new TB drug being ready for clinical use in humans by 2010 [32] Despite these impediments, there are now ∼30 new drugs for TB under development (Table 2) [29, 33–35] PA-824 (a nitroimidazole) was shown to be suc-

per-cessful against M tuberculosis in vitro and in mouse models

[36] and is now in phase II human trial stage (http://www clinicaltrials.gov/show/NCT00567840) The diarylquinoline TMC207 (also called R207910) has appeared to be particularly promising in animal studies [37, 38], and a phase IIa random- ized trial involving people with smear-positive pulmonary TB has been recently completed (http://www.clinicaltrials.gov/ show/NCT00523926) Benzothiazinones (eg, BTZ043) are a

propitious new antimycobacterial class which kill M

tubercu-losis in vitro and in mice by targeting M tubercutubercu-losis cell wall

synthesis [39], and have important potential in drug-susceptible and drug-resistant TB.

The requirement for prolonged treatment has been esized to arise from the development of a nonreplicating, phe-

hypoth-notypically drug-resistant phase of M tuberculosis driven by

hypoxia and low-level nitric oxide; these factors, which acterize the internal environment of granulomata, up-regulate dormancy genes to yield the metabolically inert state [30, 40– 42] To shorten treatment regimens, new drugs inhibiting mechanisms underlying this nonreplicating state may have promise [30].

char-A second strategy that may permit shorter TB treatment regimens is the use of drugs that are bactericidal against rapidly

metabolizing M tuberculosis Replacement of ethambutol with

moxifloxacin has been shown to significantly increase the month sputum culture conversion rate, from 63% to 80% [43] Both moxifloxacin and gatifloxacin improved the sterilizing

2-Table 1 Methods to Improve Diagnosis and Accelerate Drug Susceptibility Results

Sputum collection

Improved sputum-submission guidance If smear positive pulmonary TB case detection is impaired by

poor-quality specimen submission, case detection can be proved by provision of adequate instructions

im-Reduce number of collections from 3 to 2 Because incremental yields from subsequent sputum specimens

are small, WHO recommends examining 2 smears; this can leviate laboratory workloads, decrease time for diagnosis, and decrease the number of patients who “drop out” of the diag- nostic pathway

al-Sputum smear microscopy

Processing of sputum sample prior to smear examination (eg,

use of bleach then centrifugation or use of bleach or sodium

hydroxide then overnight sedimentation)

This is 18%–23% more sensitive than direct microscopy

Fluorescence microscopy This is 10% more sensitive than conventional microscopy; use to

determine viability of Mycobacterium tuberculosis in follow-up

sputum specimens to detect treatment failure Fluorescence microscopy using light-emitting diode light source These light sources are cheaper, last longer, and have less poten-

tial for environmental contamination than do traditional lamps used in this method

stan-Microscopic observation drug susceptibility assay Yields faster culture and DST results than do liquid or solid media

and is inexpensive, but requires inverted microscope and skilled

technician to interpret culture appearance of M tuberculosis

Thin-layer agar methodology Yields faster culture and DST results than do liquid or solid media

and is inexpensive, but requires skilled technician to recognize

M tuberculosis colony formation.

Colorimetric DST methods using redox indicators, tetrazolium

salts, or a nitrate reductase assay

These are low-cost, low-tech, and able to yield DST results within

2 weeks; potential for biosafety hazard Molecular methods

Line probe assays (eg, Genotype MTBDRplus assay [Hain] and

INNO-LiPA Rif.TB assay [Immunogenetics])

High sensitivity and specificity for detection of rifampicin (with or without isoniazid) resistance, with a 1–2 day turnaround time di- rectly for smear-positive sputum; requires DNA extraction and amplification facilities

Nucleic acid amplification tests High specificity; important role in confirming mycobacterial

iden-tity; poor negative predictive value for pulmonary and

extrapul-monary TB; updated US CDC guidelines recommend sputum M.

tuberculosis nucleic acid amplification tests for cases of

sus-pected, unconfirmed TB if results would alter management [111]

Cytokine assays: T cell interferon-g release assays Useful in targeted strategies for LTBI detection in low

TB-inci-dence settings; more specific than tuberculin skin test; cannot distinguish active from treated TB or LTBI

NOTE. From [15–17, 19, 20, 112, 113] CDC, Centers for Disease Control and Prevention; DST, drug susceptibility testing; LTBI, latent tuberculosis infection; TB, tuberculosis; WHO, World Health Organization.

activity of regimens for drug-susceptible TB [27] (gatifloxacin

has since been withdrawn from some markets on the basis of

adverse glycemic effects) Although, in a multicenter study,

moxifloxacin failed to accelerate sputum culture negativity at

2 months, 1-month culture conversions were more frequently

achieved [44] The later-generation fluoroquinolones have a

well-established place in the treatment of MDR-TB; the

pos-sibility that they might also permit shorter treatment durations

for drug-susceptible TB is lent credibility by these recent findings.

VACCINES AND ADJUNCTIVE IMMUNOTHERAPIES

The need for an improvement on bacille Calmette-Gue´rin has been long recognized as a major priority [45] The status of

Table 2 Antituberculosis Agents in Current Use and in Development

Antituberculosis agents Agent Agents

Current antituberculosis agents,

WHO classification [26]

Group 1 First-line oral antituberculosis agents Isoniazid, rifampicin, ethambutol, pyrazinamide, rifabutin

Group 2 Injectible antituberculosis agents Streptomycin, kanamycin, amikacin, capreomycin

Group 3 Fluoroquinolones Moxifloxacin, levofloxacin, ofloxacin

Group 4 Second-line oral bacteriostatic

thioaceta-Group 6 New drugs undergoing clinical

evaluation

Diarylquinolone (TMC-207, also known as R207910), troimidazopyrans (PA-824 and OPC-67683), diamine (SQ-109)

ni-Group 7 New drugs at discovery stage Benzothiazinones (eg, BTZ043), LL-3858, cell-wall

inhib-itors, multifunctional molecules, diaryl oxides, drolipoamide acryltransferase inhibitors, dipiperidine SQ-609, econazole, fatty acid synthase inhibitors, hy- drazones, InhA inhibitors, isocitrate lyase inhibitors, malate synthase inhibitors, mefloquine analogues, oxazolidinones, peptide diformylase inhibitors, pluero- mutilins, riminophenazines, thiolactomycin inhibitors, topoisomerase inhibitors, translocase inhibitors

dihy-NOTE. Multidrug-resistant tuberculosis treatment regimens should use all first-line drugs to which the organism is susceptible,

a fluoroquinolone, a daily injectible (for at least 4 months after culture conversion and for at least 6 months in total), and other

second-line drugs to provide at least 4 agents (for minimum of 18 months), with directly observed therapy, short course (DOTS), used

throughout [26, 76] In drug susceptibility testing–tailored regimens, mindfulness of the lack of universal clinical applicability of all

drug susceptibility test results and cross-resistance is required [26] From [26, 29, 33, 35, 38, 39] HIV, human immunodeficiency

virus.

promising candidate recombinant TB vaccines, including the

commencement of phase II trials of MVA85A, has been

re-viewed in detail elsewhere [45–47].

Investigation of adjunctive immunotherapies is identified as

one of several priority research areas [48–51] They offer an

attractively novel strategy to shorten TB treatment and to

con-serve antimicrobial efficacy in the face of growing resistance.

Despite negative results from many studies using inactivated

Mycobacterium vaccae as an adjunct to TB chemotherapy [52,

53], hope persists that this immunotherapy given in multiple

doses might yet have potential as an adjunctive treatment in

MDR-TB or previously treated TB [54] or as a preventative

vaccine in previously bacille Calmette-Gue´rin–vaccinated

HIV-infected persons [55, 56].

The concept of micronutrients as potential adjunctive

im-munotherapy candidates has gained currency since specific

an-timycobacterial mechanisms of action of vitamin D3in

mac-rophages (chiefly, up-regulation of LL-37/cathelicin) were

demonstrated [57, 58] The amino acid L-arginine has been

found to influence antimycobacterial T cell responses via

ex-pression of the zeta chain of the CD3/T-cell receptor complex

[59], and the metabolic product of L-arginine, nitric oxide,

mediates important macrophage antimycobacterial responses

[58] Some multiple-micronutrient interventions in TB have

been associated with benefits in patient subgroups or in

non-bacteriological end points [60–62] Whole-food nutritional support poses logistical challenges and has yet to be shown to

be cost-effective or to improve bacteriological outcomes, but

it can improve weight and possibly other parameters [63, 64] The WHO recommends nutritional support in the manage- ment of MDR TB [26], and many programs already incorporate this.

An alternative adjunctive therapeutic strategy, pression, has long been employed in TB-related meningitis and has proven to be beneficial, with corticosteroids shown to de- crease risk of death and drug-induced hepatitis [65, 66] On the basis of the hypothesis that amelioration of cytokine-me- diated pathology might be advantageous in some forms of TB, other combined immunosuppressive-therapeutic strategies have also been advocated [67, 68].

immunosup-IMPROVED MANAGEMENT AND PREVENTION

OF MDR-TB AND XDR-TB

Assigning a name to XDR-TB in 2005 brought it to public attention, accompanied by fears of a return to the preantibiotic era and the specter of untreatable TB [69] Rapid fatality in people with XDR-TB in Tugela Ferry, South Africa, illustrated the tragic consequences of this infection in the setting of high rates of concurrent HIV infection and nosocomial spread [5].

Figure 1. Proposed updates and additions to the International Standards in TB Care [14] ART, antiretroviral therapy; HIV, human immunodeficiency virus; MDR, multidrug-resistant; TB, tuberculosis; WHO, World Health Organization.

Although, in sub-Saharan Africa, this burden remains fearsome

[6, 7, 70], and although a failure to detect MDR-TB obscures

the true scale of this crisis [3], a new picture emerged during

2008 in which XDR-TB cure is a realistic aim and decreases in

MDR-TB rates can be achieved, including in resource-limited

settings [71–73] Retrospective cohort studies from diverse

lo-cations reported their experiences with MDR-TB and XDR-TB

treatment in late 2008 [22, 71, 72, 74], offering an optimistic

“potentially favorable perspective for patients” with XDR-TB

[22] (eg, cure rates of 66.3% and 60.4% for MDR-TB and

XDR-TB, respectively [72]) Level 1 (randomized, controlled trial–

derived) evidence is required, as articulated by the Cambridge

Declaration on clinical trials for drug-resistant TB [75], but

meta-analysis of retrospective observational cohort studies was

recently performed This has identified the WHO

recommen-dations of a treatment duration of ⭓18 months after culture

conversion and administration of DOT throughout as the

fac-tors associated with the greatest chance (almost 70%) of

treat-ment success [76] Drug susceptibility testing–tailored regimens

were associated with nonstatistically significantly better

out-comes than were standardized regimens, and inconsistent

re-porting of HIV status rendered examination of this variable

difficult [76] MDR-TB and XDR-TB treatment programs

pro-viding additional measures, such as nutritional and economic

assistance for patients, have reported high rates of cure and

treatment completion [71, 72], but the relative efficacy of such

supports is unknown High rates of successful treatment

out-come may not be widely generalizable; major differences in

outcomes are seen in South Africa, even accounting for HIV

infection, possibly attributable to low use of quinolones; patient

factors (higher use of alcohol, tobacco, and other drugs;

mal-nutrition; and host immunity) and/or M tuberculosis strain

factors (differing virulence) [70], although meta-analysis did not find these factors to have a significant impact on MDR-

TB outcome [76].

Even the best outcomes for MDR-TB treatment remain stantially worse than the WHO’s cure target of 85% for drug- susceptible TB, and the pool of undiagnosed MDR-TB and XDR-TB seriously threatens control efforts Nevertheless, good cure rates provide a notably more positive outlook than the dire reports from only 2–3 years ago Despite the expenses of MDR-TB treatment, modeling including drug, laboratory, and personnel costs indicates that MDR-TB treatment can be highly cost-effective [77] There is a clear imperative for managing drug-resistant TB in accordance with current guidelines (eg, in DOTSPlus projects, accessing second-line anti-TB drugs through the Green Light Committee) [26] while not diverting funds away from the core business of basic TB service provision.

sub-An additional cause for optimism is the recent decrease in MDR-TB rates documented in Estonia, Latvia, Hong Kong, and the United States [73]; the next important step is to identify the factors responsible for these successes Infection control is emerging as a critical focus for MDR-TB and XDR-TB pre- vention, because they are frequently nosocomially transmitted [4–6, 78], requires renewed enthusiasm for more stringent re- spiratory infection control This need not be complicated: mod- eling of XDR-TB transmission in Tugela Ferry indicated that appropriate use of existing resources (a combination of use of face masks, reduced duration of hospitalization, and a shift to outpatient therapy) could prevent nearly one-third of XDR-TB

Table 3 Summary of Recommendations for Antiretroviral Therapy (ART) in Patients with Concurrent Human

Immunodeficiency Virus (HIV) Infection and Tuberculosis (TB)

CD4 T cell count

ART recommendation

Timing of ART initiationaDrug-susceptible TB Multidrug-resistant TB

NOTE. The recommended first-line ART regimen is efavirenz (600 mg daily) plus 2 nucleoside reverse-transcriptase inhibitors,

with a rifampicin-based TB regimen given 5–7 times weekly [91, 92] The rationale for using ART to prevent TB and to improve TB

treatment outcome in persons with HIV infection is based on evidence that ART reduces the risk of developing active TB [85, 86]

and improves survival when it is started during TB treatment, compared with if it is deferred [93–96], with the benefits of early ART

initiation in people with TB outweighing the disadvantage of potential increased occurrence of immune reconstitution disease [7, 106].

Furthermore, ART achieves as-good virological and immunological responses as in people without TB [106].

a

From [7, 89, 91].

cases [79] Elsewhere, natural ventilation achieved by opening

windows and doors was estimated to achieve lower TB

trans-mission than costly, maintenance-requiring mechanical

venti-lation systems [80] Recent revisitation of 1950s experimental

designs, using exhaust air from a TB ward passed into guinea

pig enclosures, demonstrated that low-cost ultraviolet lights

prevented 70% of TB infections, and negative air ionization

prevented 60% of TB infections [81] Nosocomial XDR-TB

transmission can occur even with good ventilation, limited

pa-tients per room, and ultraviolet lamps [4] Nevertheless,

evi-dence indicates that the ISTC [14] should require an additional

18th standard: that respiratory infection control measures

should be implemented in facilities treating patients with newly

diagnosed smear-positive TB, especially in areas with a high

prevalence of MDR-TB or XDR-TB.

IMPROVED HIV-TB MANAGEMENT

HIV infection increases the risk of latent TB reactivation

20-fold [82, 83], and in southern Africa, TB is the leading cause

of death among people with HIV infection [84] Identifying

HIV infection presents an important TB control opportunity

through the use of antiretroviral therapy and isoniazid

preven-tive therapy, both of which reduce the risk of developing acpreven-tive

TB and require continued up-scaling [85–88] Advances in the

understanding of management of concurrent HIV infection and

TB include improved guidelines on HIV testing in persons with

TB (ie, provider-initiated opt-out testing of all people with

newly diagnosed TB [7, 89–92]), growing knowledge of optimal

antiretroviral therapy regimens to use in combination with

an-timycobacterial agents [7, 89–92], and timing of antiretroviral

therapy commencement in relation to TB [7, 89, 91, 93–96].

Benefits of isoniazid preventive therapy are also evident [97],

although details, such as how to confidently exclude active TB,

safety in combination with antiretroviral therapy, and the

rec-ommended duration (eg, 12 months, lifelong, or base on CD4

cell count), are areas of ongoing research (http://www.clinical trials.gov/NCT00463086).

First-line antiretroviral therapy recommended for persons with concurrent HIV infection and TB by Centers for Disease Control and Prevention and WHO comprises standard-dose efavirenz plus 2 nucleoside reverse-transcriptase inhibitors [91, 92], on the basis of the understanding that the 20% lower serum efavirenz concentration caused by rifampicin remains effective

in suppressing HIV replication [98, 99] Efavirenz may be safer

in pregnancy than hitherto realized [92, 100, 101], although it remains a Category D listing Nevirapine concentrations are more likely to be subtherapeutic in combination with rifam- picin [102], and virological failure risk may be higher [103] Despite this, nevirapine-based antiretroviral therapy is consid- ered a suitable choice for second- or third-line treatment if efavirenz is contraindicated or unavailable and if rifamycins with less potency in inducing cytochrome P450 enzymes (ri- fapentine or rifabutin) are unavailable (as is generally the case where TB is endemic) [91, 92].

Determining optimal timing for antiretroviral therapy mencement after initiation of TB treatment is challenging be- cause of drug toxicities, interactions, the heavy pill burden and attendant adherence risk, and immune reconstitution inflam- matory syndrome [104, 105] Although immune reconstitution inflammatory syndrome may increase with wider and earlier antiretroviral therapy use [94], it has not been associated with increased mortality, and to date, the risks appear to be out- weighed by the benefits of early antiretroviral therapy [7, 106] Recent cohort studies and preliminary data from one trial in- dicate that the optimal strategy is to begin antiretroviral therapy during TB treatment and that integration of HIV and TB care offers valuable benefits [93–96] WHO guidelines recommend commencement of antiretroviral therapy 2–8 weeks after ini- tiation of TB treatment if the CD4 cell count is ! 350 cells/mm 3

com-or unknown [7, 89, 91] Additional data, including data from

the SAPIT (Starting Antiretrovirals at Three Points in

Tuber-culosis Therapy) trial [96], should provide further clarity On

the basis of the evidence summarized above, ISTC Standard

13, which recommends antiretroviral therapy in selected

pa-tients with concurrent HIV infection and TB, can be updated

to incorporate advice regarding antiretroviral therapy regimen

selection and timing of commencement (Figure 1 and Table

3).

TOWARD THE STABILIZATION OF THE

“GLOBAL EMERGENCY”

The reported number of TB cases per capita has been decreasing

globally since 2003, and funding for TB control has improved,

peaking in 2008 at US $3.3 billion [8] Although the challenges

posed by HIV infection and MDR-TB remain formidable

worldwide, 3 of the 6 WHO regions (the Americas, the Eastern

Mediterranean, and South-East Asia) will meet 2015 targets for

reductions in TB case numbers and fatalities [3] Progress in

industrialized countries includes downward trends in TB rates

in Indigenous populations Over the past 20 years, the TB

incidence has decreased among Australian Aborigines [107],

Canadian First Nations populations [108, 109], and Native

Americans [110], attributed to factors that include

improve-ments in case finding and treatment in the early 1990s [108,

109] These figures do not permit relaxation in TB control but

illustrate that, where adequate resources can be directed toward

at-risk populations, major benefits can result, and downward

trends ought to be maintainable.

New challenges continually arise in TB, but these become

opportunities for the recognition and development of

inno-vative TB control strategies For these advances to translate into

mainstream practice in a timely manner, national TB programs

need to embrace new evidence, and clinicians in areas where

TB is endemic require workable mechanisms to achieve

con-tinuing education alongside their heavy workloads Such

mech-anisms include the more vigorous promotion of international

standards at a national level and timely implementation by

practitioners The 2006 ISTC [14] has proven to be useful in

convincing national professional societies and academic

insti-tutions to support implementation of internationally

recog-nized standards of TB care [8] Such has been the rapidity of

progress in the past 3 years that we suggest that the ISTC be

updated to incorporate the elements summarized in Figure 1.

In many parts of the world, such strategies may appear

un-realistic However, even in circumstances of poverty or

insta-bility, there can be scope for optimization of resource allocation

and mobilization of political will to allow modern TB

man-agement to be adopted where it is needed most Enthusiasm

for adopting such changes can be generated by disseminating

cost-effective TB success stories Despite major new challenges,

wider incorporation of recent advances, and further

optimi-zation of DOTS programs provide grounds for improved TB control.

Acknowledgments

We thank the anonymous reviewers for their very helpful contributions

to the final manuscript.

Financial support. The Australian National Health and Medical search Council.

Re-Potential conflicts of interest. All authors: no conflicts.

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Chapter 2: Introduction 1: Tuberculosis

Manuscript 2: Ralph A, Kelly P, Krause V What's new in TB? Australian Family Physician 2009;

38(8):578-585

<see paper next page>

thEmE infectionS tHAt LASt

Appreciation of what’s new in tuberculosis (tB) requires a

perspective of what’s old: Mycobacterium tuberculosis (mtB) and other members of the mtB complex (Table 1) have been

infecting humans since antiquity 1,2 Being therefore consummately adapted to life within the human host, 3 mtB infects up to one-third of the global population, is characterised by a dormant phase which confounds diagnosis and control, and in 2006 accounted for an estimated 9.2 million new cases and 1.7 million deaths worldwide 4

Australia largely avoided the late 20 th century global TB resurgence, which prompted the declaration of TB as a ‘global emergency’ by the World Health Organization (WHO) in 1993 The millennium development goals set a target of reducing prevalence and death rates of TB by 50% by 2015 Although many countries are on track to attain these rates, highest burden countries, notably in sub-Saharan Africa where multidrug resistant TB (MDR-TB) and the overlap of TB and HIV epidemics pose crippling challenges, are not 4

Against this background, Australia in 2006 reported 1201 TB cases, an incidence of 5.8 per 100 000 population, 5 with preliminary

2008 figures being similar 6 The national strategic plan for TB control recognises the importance of favourable socioeconomic circumstances; successful post-World War II national TB campaigns; specialised, multidisciplinary, free TB services; and effective premigration screening as contributors to Australia’s low TB rates 7 New challenges faced by Australian practitioners include addressing high rates of TB (~1360/100 000) in Indonesian fishermen entering Northern Territory waters, 8 and MDR-TB (25% of cases) in Papua New Guinean nationals seeking treatment in the Torres Strait protected zone 9 This provides a preview of cases Australian practitioners are likely to be more frequently presented with in coming years as the distribution of MDR-TB continues to expand.

Tuberculosis treatment in Australia is conducted by specialists within centralised, coordinated TB services Failure to manage TB in this fashion is associated with higher risks of treatment failure and emergence of drug resistance 10 However, general practitioners have the key responsibilities of recognising at risk people and coordinating care for affected families In particular, the most vital contribution GPs can make is to avoid TB diagnostic delay by sending sputum specimens

Background

Australia has among the world’s lowest rates of tuberculosis

(TB) However, it remains a leading global cause of morbidity

and mortality In Australia, TB remains more common in

Indigenous than non-Indigenous Australians, and rates are rising

among migrants, reflecting changing immigration patterns and

rising rates in their homelands

Objective

This article reviews recent developments in TB of relevance to

Australian general practice and provides an update of advances

in the diagnosis and management of TB, and the role of the

general practitioners in co-managing people with TB.

Discussion

First hand experience with imported multidrug resistant TB

(MDR-TB) is increasing and is anticipated to rise in Australia

The reach of extensively drug resistant TB is also expanding

Although standard guidelines for management of drug

susceptible TB remain unchanged, recent progress in the

understanding, diagnosis and management of TB has occurred,

driven by the need to respond to the challenges of MDR-TB and

Anna ralph

BMedSci, MBBS, MPH, DTM&H, FRACP, is a PhD Candidate, National Centre for Epidemiology and Population Health, Australian National University and Menzies School of Health Research, and a locum infectious diseases physician, Alice Springs, Northern Territory

anna.ralph@anu.edu.au

for specific examination for acid fast bacilli (AFB) and reviewing chest

radiograph findings in at risk people with suspicious cough (>2 weeks

or ‘chronic pneumonia’) This review presents recent developments

in TB relevant to Australian general practice Comprehensive TB

management guidelines are provided elsewhere (see Resources)

Who is at risk in Australia?

Tuberculosis requires particular consideration in migrants and

refugees from high incidence countries Approximately 85% of new

Australian TB cases occur in people born overseas 5 Highest global

per capita TB rates occur in sub-Saharan Africa, 4 reflected in high TB

notification rates in Australians of sub-Saharan origin 5 Commonest

countries of origin of people with TB in Australia (consistent with

relative sizes of migrant populations) are India, Vietnam, the

Philippines, China and Indonesia 5 Tuberculosis cases in migrants are

usually attributable to reactivation of latent TB infection (LTBI) (often

within the first 2 years after migration), 11 with smaller contributions

from local transmission within migrant communities, and newly

acquired infections after visits home 12 Negative premigration

or arrival TB screening does not therefore negate the possibility

of subsequent TB.

Indigenous Australians (in some communities more than others)

are at higher risk than non-Indigenous Australian born people (6.6

vs 0.9 per 100 000) 5 Other commonly identified TB risk factors in

Australia are household contact with TB, or residence in a TB high

prevalence country for more than 3 months 5 Returned travellers

uncommonly present with TB 13

Human immunodeficiency virus confers the greatest single

risk for TB, increasing the chance of latent TB reactivation up to

20-fold 14,15 In Australia, HIV-TB co-infection is uncommon, but the

reporting of HIV status in people with TB, at 37%, is much lower

than recommended 5 A new diagnosis of TB must prompt an offer

of HIV testing as per local and international recommendations 16–18

Other forms of immunosuppression also significantly increase the

likelihood of LTBI reactivation In people with LTBI, such as migrants

and indigenous people from high TB burden communities, chronic

renal failure and high dose corticosteroid use approximately doubles

the risk of developing active TB, while TNF-α blockers (eg infliximab)

increase the risk five-fold compared with the comparative population

risk of LTBI reactivation 19,20

These at risk groups require screening for LTBI if asymptomatic

(see below and Table 2), or investigation for active pulmonary or extra

pulmonary TB if symptomatic with a clinically relevant syndrome

People with LTBI at risk of progression to active TB, require LTBI

treatment (Table 3) Detailed screening and LTBI treatment guidelines

are provided elsewhere 11,21–25

What’s new in tB diagnostics?

Globally, the commonest method for diagnosing TB remains sputum microscopy only; therefore improved access to inexpensive diagnostics is

a priority in under resourced settings There has been promising progress

in the development of such tests, including improved microscopy and culture techniques, and rapid molecular methods for detection of rifampicin and isoniazid resistance gene mutations 26 These can provide rifampicin/isoniazid susceptibility results within 1–2 days, compared with approximately 42 days using liquid culture media 27 A reliable point

of care test such as antigen detection on blood or sputum would be the

‘holy grail’ of TB diagnostics; such tests are under investigation 28 but not yet commercially available Nucleic acid amplification tests, including polymerase chain reaction (PCR), have high specificity Although negative predictive value is low, the possibility of a positive result in smear negative disease can allow more rapid diagnosis while awaiting culture;

recently updated Centres for Disease Control (USA) guidelines therefore recommend sputum MTB nucleic acid amplification testing where available and affordable, in cases of suspected, unconfirmed TB, if results would alter management 29

interferon gamma release assays

Of more relevance in Australia are interferon gamma release assays (IGRA), such as QuantiFERON-TB Gold, as potential supplements

or alternatives to tuberculin skin testing (TST) for detecting TB exposure Currently, Australia’s National Tuberculosis Advisory Committee discourages use of these tests in clinical settings pending further research into sensitivity, specificity and cost effectiveness

(Table 2), favouring use of clinical history and TST.21,30 Like the TST, IGRA detect T-cell responsiveness to MTB antigens, but this is measured on a blood sample as interferon (IFN)-γ production rather than an in vivo skin reaction, and the antigens used to elicit the response are more specific to MTB than those contained in purified protein derivative Some diagnostic algorithms incorporate these tests

Vicki Krause

MD, DTM&H, FAFPHM, is Director, Centre

for Disease Control and Head, Tuberculosis/

Leprosy Services, Department Community

and Families, Darwin, Northern Territory.

Table 1 Mycobacterium TB and other members of the MTB complex

mycobacterium genus

• Gram positive, acid fast bacilli Those pathogenic to humans include mycobacteria of the MTB complex, pathogenic non-

tuberculous mycobacteria (NTM) and M leprae

• Tuberculosis causing group – MTB complex:

– M tuberculosis – M bovis – M africanum – M bovis Bacillus Calmette Guerin (BCG) (attenuated

vaccine strain, able to cause disseminated tuberculosis in immunocompromised hosts)

– Uncommon: M microti, M bovis subspecies capra,

M tuberculosis subspecies canettii, M pinnipedii

What’s new in tB?

thEmE

as adjuncts to, 31 or replacements of, 32,33 TST, hence some familiarity

with this test is required

A ‘take home message’ is that a positive result in either IGRA or TST

does not confirm, and a negative test does not exclude, TB exposure.

What’s new in tB treatment?

Standard treatment regimens for active and latent disease caused

by drug susceptible MTB have not changed in Australia in recent

decades (Table 3), however, new developments are discussed below

new drugs for tB

The drought in new TB drug discovery appears to be breaking, with

about 30 new agents in the developmental pipeline 34,35 A metronidazole

related antibiotic, PA-824, has been found to be successful against MTB

in vitro and in mouse models 36 and is now in phase 2 human trials

Novel agents targeting specific MTB genes are under investigation 37

Quinolones, with a well established place in the treatment of MDR-TB,

are under investigation for their potential to shorten treatment durations

in drug sensitive TB 38 Of critical importance is the need to limit misuse

of new drugs, eg use of quinolones as monotherapy in TB misdiagnosed

as pneumonia is associated with development of resistance and

delayed TB diagnosis 39

hiV-tB co-infection management

Traditionally, delayed commencement of antiretroviral treatment (ART) was recommended in HIV-TB co-infection due to overlapping drug toxicities, drug interactions, and the potential for paradoxical worsening of TB pathology due to immune restoration inflammatory syndrome 40 However, it is becoming clearer that benefits of early ART outweigh these risks, and that despite rifampicin induced increased clearance of non-nucleoside reverse transcriptase drugs (efavirenz/ nevirapine), serum levels of these drugs can remain adequately efficacious to permit their use 41 Current guidelines recommend starting ART within 2–8 weeks of TB treatment initiation if CD4 <200, and after 8 weeks if CD4 200–350, preferably using an efavirenz based regimen 17,40,41

The importance of TB screening in people with HIV (eg using

a combination of symptom check, sputum microscopy, TST), and isoniazid preventive therapy if LTBI is identified, are increasingly recognised as critical and underutilised public health measures 42

mDr-tB management

Multidrug resistant TB was initially recognised to result from poor treatment programs with low adherence, leading to selection of drug resistance mutations in infecting MTB strains 43 However, it

Table 2 Advantages and disadvantages of interferon gamma release assays 29,57–62

iGrA disadvantages compared with tuberculin skin testing

Currently less collective experience with IGRA exists, and there are uncertainties in how to interpret results, eg when there is discordance between IGRA and TST, discordance between different IGRA types, and when serial IGRA results change (reversion/conversion)

Requires blood taking, which in infants (a common target group for screening) is more difficult, and often not done by rural/remote health workers and registered nurses

Loss of patient educational opportunities which are provided when TB nurse performs and reads TST

IGRA possibly less sensitive

IGRA test kit more expensive than PPD

Reversions from positive to negative can occur over time and are difficult to interpret (but usually only occur when the initial reading was low-positive)

Requires laboratory reagents and staff not generally available in resource limited settings, thereby restricting accessibility in remote settings Indeterminate results can occur, eg due to failures of controls, inadequate cell separation, cross contamination

Greater incidence of discordance between IGRA and TST in children (usually TST positive, IGRA negative)

iGrA advantages compared with tst

IGRA only target antigens present in MTB ‘region of difference 1’ (RDI1) such as CFP10 and ESAT6, which are not shared by other

mycobacteria except M kansasii, M marinum and M szulgai, thereby increasing the specificity of the test

Unaffected by prior BCG vaccination, for same reason as above (RDI antigens not present in M bovis BCG)

Only requires one clinic attendance if negative

Disadvantages of both iGrA and tst

Unable to distinguish active from latent disease

False negatives occur especially in immunosuppression

No gold standard for LTBI diagnosis, therefore the true sensitivity and specificity of both tests cannot be accurately evaluated

A niche for iGrA use?

QTF-G may be strategically used in settings such as previously BCG vaccinated TB contacts with a positive skin test, and BCG vaccinated health care workers in low TB incidence countries who require repeat testing

TST= tuberculin skin test using purified protein derivative (PPD) (also known as Mantoux test)

What’s new in tB? thEmE

is increasingly found to be a primary transmitted organism in high

MDR burden areas, emphasising the vital importance of infection

control 9,44,45 Multidrug resistant TB treatment regimens (Table 3)

are prolonged, costly, and associated with significant side effects

and adherence difficulties However, well functioning programs,

especially those incorporating the WHO recommendations of ≥18

months treatment duration after culture conversion and directly

observed therapy throughout, report cure rates of >60% 46 Similar

success rates have recently been reported for extensively drug

resistant TB (XDR-TB) in some programs 47 (Note: XDR-TB = resistant

to rifampicin, isoniazid, any fluoroquinolone and at least one second

line injectible agent such as amikacin, capreomycin or kanamycin)

This has overturned the spectre of ‘untreatable TB’ which has

surrounded XDR-TB, 48 and comprehensive new recommendations for

combating XDR-TB are available 49

how can GPs care for patients with tB?

Although speciality TB treatment units have the responsibility

for reporting and treating TB, managing medication adverse events

and ensuring adequate contact tracing (see Resources), GPs

are at the forefront of having to suspect TB and LTBI, and integrate

TB care with other medical needs of the affected individual and

their family

Avoid diagnostic delay

By considering pulmonary TB in people with symptoms (eg cough

>2–3 weeks, fever ≥3 weeks, loss of >10% body weight) and epidemiological risk factors, GPs have the valuable opportunity

to avoid diagnostic delay Delayed diagnosis aggravates the individual’s morbidity, increases public health risk, and complicates the subsequent contact tracing required

As a negative smear does not exclude pulmonary TB, clinical suspicion

in a person from a TB endemic country warrants referral to TB services

(see Resources), regardless of AFB sputum smear result

infection control

General practices require a policy for ensuring adequate respiratory precautions for people with suspected or confirmed infectious pulmonary TB attending their practice, or whom they care for in nursing homes, prisons or other institutions, including avoidance of communal areas and use of face masks 22,24

Table 3 Anti-TB agents and treatment strategies

Anti-tB agents, WhO classification 63 Drug

Group 1 First line oral antituberculosis agents Isoniazid, rifampicin, ethambutol, pyrazinamide, rifabutin

Group 2 Injectable antituberculosisagents Streptomycin, kanamycin, amikacin, capreomycin

Group 4 Second line oral bacteriostatic antituberculosis agents Ethionamide, protionamide, cycloserine, terizidone,

para-aminosalicylic acid Group 5 Antituberculosis agents with unclear efficacy Clofazimine, amoxicillin/clavulanate, linezolid, thioacetazone,

imipenem/cilastin, high dose isoniazid, clarithromycin

standard first line tB treatment

Rifampicin, isoniazid*, pyrazinamide, ethambutol daily or thrice weekly for 2 month ‘intensive phase’ then rifampicin and isoniazid daily or

thrice weekly for 4 month ‘continuation phase’ Dosing (see reference 23)

standard ltBi treatment**

Isoniazid* daily 9 months 23–25

mDr-tB treatment strategies

Two phase regimen using at least five drugs to which the infecting isolate is sensitive Drugs include remaining first line drugs to which

the organism is sensitive (ethambutol and/or pyrazinamide) plus a quinolone (descending order of potency against MTB: moxifloxacin =

gatifloxacin > levofloxacin > ofloxacin = ciprofloxacin) plus an injectible agent from Group 2 above, plus others as required High dose

isoniazid may retain efficacy against MDR isolates with low level isoniazid resistance 64,65

Phase 1: includes injectible agent, minimum 6 month duration and at least 4 months past culture conversion

Phase 2: after cessation of the injectible agent, continued for at least 18 months after culture conversion 63,66

ltBi treatment where infecting strain is thought to be mDr-tB

No Level 1 evidence Two drug regimen tailored to the sensitivity profile of the MTB isolated from the contact may be efficacious, eg

pyrazinamide + ethambutol or a quinolone 6–12 months; 65 alternatively, a monitoring approach may be appropriate, especially in children

* Vitamin B6 (pyridoxine) 25 mg/day routinely accompanies isoniazid to reduce the incidence of peripheral neuropathy

** Combination therapy is needed in active but not latent TB, as active TB is characterised by high bacillary numbers, hence the number of bacilli with

spontaneously arising resistance mutations at baseline, which can be selected out by inadequate regimens, is much greater than in LTBI 67

What’s new in tB?

thEmE

Avoid drug interactions

Rifampicin is a potent inhibitor of cytochrome P450 isoenzymes,

especially CYP3A4 and CYP2C8/9, and therefore great attention

to other medications metabolised by these enzymes, especially

anticonvulsants, oral contraceptives and warfarin, is required.

nutrition

Malnutrition contributes to TB risk and complicates active TB 50

Specific micronutrients with immunological functions such as vitamin

D may be of particular importance, 51,52 but trial outcomes examining

use of these agents as supplements in TB treatment are pending

Food scarcity is obviously less problematic in Australia than in high

TB burden countries, but nutritional optimisation and replacement of

deficient nutrients in individuals with TB is in keeping with current

WHO recommendations 53

smoking cessation

Active and passive smoking are associated with elevated TB risk and

worse outcomes from TB infection 54 Smoking cessation is therefore an

important potential intervention area, although the impact of quitting

after diagnosis on individual patient outcomes remains to be determined

Psychological support and adherence help

Psychological and practical supports are key requirements of TB

care Tuberculosis remains deeply stigmatised in many societies, and

confinement in respiratory isolation can be traumatising 55 A diagnosis

of TB can therefore require management of negative psychological

effects The prolonged duration of therapy requires assiduous

measures to promote adherence The most widely used of these

is the WHO sanctioned ‘DOTS’ (directly observed therapy – shourt

corse) Other adherence promoting measures include addressing

financial costs of leave from work by assisting in accessing short

term disability pensions, addressing any problematic beliefs about

TB including those to do with law and migration status, and providing

ongoing education about the need to continue treatment even after

symptom resolution 56

conclusion

Important new developments in TB diagnosis and treatment

have occurred in recent years These include the availability of

new diagnostic tests, updated guidelines on managing HIV-TB

co-infection, new data showing better prognoses for people with

MDR-TB/XDR-TB, and renewed emphasis on the importance of

infection control Australia remains in the fortunate position of

having very low TB rates by global standards, low drug resistance

(although increasing cases are projected), infrequent cases of HIV

co-infection, and access to MTB culture and susceptibility testing

Maintaining this position despite the high global burden of TB

requires ongoing timely TB screening, a low threshold for considering

the diagnosis of active TB in people at risk, and psychosocial support

to assist adherence to treatment

resources

Australian state and territory tB contacts

• Australian Capital Territory Tuberculosis Service, c/o Thoracic Unit, The Canberra Hospital Phone 02 6244 2066

• New South Wales Tuberculosis Program, NSW Department of Health Phone 02 9391 9277

• Northern Territory Tuberculosis Unit, Centre for Disease Control Phone 08

8922 8804

• Queensland Tuberculosis Control Centre Phone 07 3896 3939

• South Australian Tuberculosis Services, Royal Adelaide Hospital Chest Clinic Phone 08 8222 4867

• Tasmanian Tuberculosis Services, Southern Region – Respiratory Unit, Royal Hobart Hospital, phone 03 6222 7353; Northern Region – Respiratory Unit, Launceston General Hospital, phone 03 6348 7708; North-Western Region – Chest Clinic, Community Nursing, phone 03 6421 7700

• Victorian Tuberculosis Control Section, Department of Human Services Phone 03 9096 5110 or 1300 651 160

• Western Australian Tuberculosis Control Program, Perth Chest Clinic Phone 08 9219 3222.

selected guidelines and resources

• Australian National Tuberculosis Advisory Committee (NTAC) Available

at about.htm

www.health.gov.au/internet/main/publishing.nsf/Content/cdna-ntac-• Management, control and prevention of tuberculosis Guidelines for health care providers (2002–2005) Rural and Regional Health and Aged Care Services Division, Victorian Government Department of Human Services, 2002 Available at www.health.vic.gov.au/ data/assets/ pdf_file/0006/19986/tb_mgmt_guide.pdf

• Centre for Disease Control Northern Territory Guidelines for the control of tuberculosis in the Northern Territory 4th edn, 2008 Department of Health and Community Services, Northern Territory Government Available at www.health.nt.gov.au/library/scripts/objectifyMedia.aspx?file=pdf/25/05 pdf&siteID=1&str_title=Tuberculosis Control Guidelines.pdf

• Australasian Society for Infectious Diseases Writing Group Diagnosis, management and prevention of infections in recently arrived refugees

2002 Available at www.asid.net.au/downloads/RefugeeGuidelines.pdf

• World Health Organization TB publications Available at www.who.int/tb/ publications/en/index.html

• ment and monitoring: Questions & answers 2nd edn, 2004 Available at whqlibdoc.who.int/publications/2004/9241546034.pdf

World Health Organization Toman’s tuberculosis case detection, treat-• Stop TB Partnership Available at www.stoptb.org/

Fact sheets for patients

• www.health.vic.gov.au/ideas/diseases/tb_facts

• www.health.nt.gov.au/Centre_for_Disease_Control/Publications/CDC_ Factsheets/index.aspx.

Conflict of interest: none declared.

Acknowledgments

Anna Ralph is supported by the National Health and Medical Research Council (NHMRC) and a Royal Australasian College of Physicians – Covance Award Paul Kelly is supported by NHMRC We thank the members of the National TB Advisory Committee for providing the contacts listed in the resources table.

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